{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,23]],"date-time":"2026-07-23T01:42:15Z","timestamp":1784770935013,"version":"3.55.0"},"reference-count":53,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2025,12,23]],"date-time":"2025-12-23T00:00:00Z","timestamp":1766448000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Cannabidiol (CBD) is a non-psychoactive phyto-cannabinoid with numerous pharmacological potentials. CBD is a lipophilic drug with poor and varied bioavailability due to its low water solubility and extensive first-pass metabolism, and it is highly affected by the presence of food. A self-emulsifying drug delivery system (SEDDS) was developed to improve the aqueous solubility and oral bioavailability of CBD. The formulation strategy involved incorporating excipients that maintain drug solubility under both fasted and fed conditions, while potentially mitigating first-pass metabolism to enhance overall bioavailability and dose proportionality. Caproyl\u00ae 90, Tween\u00ae 20, and Transcutol\u00ae HP were selected as the oil phase, surfactant, and cosolvent, respectively, for formulation preparation and screening. CBD SEDDS formulations containing Caproyl\u00ae 90 \u226420% w\/w and Tween\u00ae 20 above 40% w\/w yield particles below 200 nm. CBD SEDDS with Tween\u00ae 20 65% w\/w or higher showed in vitro release of more than 90%. After in vitro digestion, CTT1, CTT4, and CTT8 remained stable under gastrointestinal conditions and maintained CBD solubility of at least 50%. The most promising formulations, CTT4 and CTT8, were used for in vivo evaluations. Both formulations showed similar in vitro results; however, in vivo, CTT4 demonstrated 2.4-fold higher bioavailability than CTT8. Overall, optimizing the level of inhibitory surfactant appears to be a promising strategy for improving CBD bioavailability.<\/jats:p>","DOI":"10.3390\/biom16010021","type":"journal-article","created":{"date-parts":[[2025,12,23]],"date-time":"2025-12-23T10:57:18Z","timestamp":1766487438000},"page":"21","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Development and Characterization of Cannabidiol Self-Emulsifying Drug Delivery System: In Vitro and In Vivo Evaluation"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-6290-8599","authenticated-orcid":false,"given":"Nourhan","family":"Mostafa","sequence":"first","affiliation":[{"name":"Department of Pharmaceutics and Drug Delivery, School of Pharmacy, University of Mississippi, University, MS 38677, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Iman E.","family":"Taha","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutics and Drug Delivery, School of Pharmacy, University of Mississippi, University, MS 38677, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Noha M.","family":"Abourobe","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutics, Faculty of Pharmacy, Suez Canal University, Ismailia 41522, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9013-1327","authenticated-orcid":false,"given":"Eman A.","family":"Ashour","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutics and Drug Delivery, School of Pharmacy, University of Mississippi, University, MS 38677, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,12,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"8342","DOI":"10.1002\/jcp.27725","article-title":"Medical Cannabis: A plurimillennial history of an evergreen","volume":"234","author":"Pisanti","year":"2019","journal-title":"J. Cell. Physiol."},{"key":"ref_2","first-page":"363","article-title":"On the preparations of the Indian hemp, or Gunjah: Cannabis indica their effects on the animal system in health, and their utility in the treatment of tetanus and other convulsive diseases","volume":"5","year":"1843","journal-title":"Prov. Med. J. Retrosp. Med. Sci."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Hanu\u0161, L.O., and Maslov, L.N. (2025). A Brief but Concise History of the Discovery and Elucidation of the Structure of the Major Cannabinoids. Psychoactives, 4.","DOI":"10.20944\/preprints202502.2113.v1"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"118359","DOI":"10.1016\/j.indcrop.2024.118359","article-title":"Health benefits, pharmacological properties, and metabolism of cannabinol: A comprehensive review","volume":"213","author":"Khouchlaa","year":"2024","journal-title":"Ind. Crops Prod."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1039\/CT8997500020","article-title":"III.\u2014Cannabinol. Part I","volume":"75","author":"Wood","year":"1899","journal-title":"J. Chem. Soc. Trans."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"196","DOI":"10.1021\/ja01858a058","article-title":"Structure of cannabidiol, a product isolated from the marihuana extract of Minnesota wild hemp I","volume":"62","author":"Adams","year":"1940","journal-title":"J. Am. Chem. Soc."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"223","DOI":"10.31887\/DCNS.2020.22.3\/mcrocq","article-title":"History of cannabis and the endocannabinoid system","volume":"22","author":"Crocq","year":"2020","journal-title":"Dialogues Clin. Neurosci."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"S163","DOI":"10.1038\/sj.bjp.0706406","article-title":"Cannabinoid pharmacology: The first 66 years","volume":"147","author":"Pertwee","year":"2006","journal-title":"Br. J. Pharmacol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"S5","DOI":"10.1097\/j.pain.0000000000002268","article-title":"Cannabinoids, the endocannabinoid system, and pain: A review of preclinical studies","volume":"162","author":"Finn","year":"2021","journal-title":"Pain"},{"key":"ref_10","first-page":"607","article-title":"Review of the endocannabinoid system","volume":"6","author":"Lu","year":"2021","journal-title":"Biol. Psychiatry Cogn. Neurosci. Neuroimaging"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Navarrete, F., Garc\u00eda-Guti\u00e9rrez, M.S., Jurado-Barba, R., Rubio, G., Gasparyan, A., Austrich-Olivares, A., and Manzanares, J. (2020). Endocannabinoid system components as potential biomarkers in psychiatry. Front. Psychiatry, 11.","DOI":"10.3389\/fpsyt.2020.00315"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2778","DOI":"10.3390\/ijms21082778","article-title":"A guide to targeting the endocannabinoid system in drug design","volume":"21","author":"Stasiulewicz","year":"2020","journal-title":"Int. J. Mol. Sci."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1159\/000540353","article-title":"Development and in vitro evaluation of cannabidiol mucoadhesive buccal film formulations using hot-melt extrusion technology","volume":"7","author":"Taha","year":"2024","journal-title":"Med. Cannabis Cannabinoids"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Atalay, S., Jarocka-Karpowicz, I., and Skrzydlewska, E. (2019). Antioxidative and anti-inflammatory properties of cannabidiol. Antioxidants, 9.","DOI":"10.3390\/antiox9010021"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"439","DOI":"10.1111\/bcpt.13710","article-title":"A narrative review of molecular mechanism and therapeutic effect of cannabidiol (CBD)","volume":"130","author":"Peng","year":"2022","journal-title":"Basic Clin. Pharmacol. Toxicol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"4379","DOI":"10.3390\/cimb46050266","article-title":"Modulation of oxidative stress and Neuroinflammation by Cannabidiol (CBD): Promising targets for the treatment of Alzheimer\u2019s disease","volume":"46","author":"Hickey","year":"2024","journal-title":"Curr. Issues Mol. Biol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"e00682","DOI":"10.1002\/prp2.682","article-title":"Diversity of molecular targets and signaling pathways for CBD","volume":"8","author":"Devi","year":"2020","journal-title":"Pharmacol. Res. Perspect."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1684\/epd.2020.1135","article-title":"The proposed mechanisms of action of CBD in epilepsy","volume":"22","author":"Gray","year":"2020","journal-title":"Epileptic Disord."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1888","DOI":"10.1056\/NEJMoa1714631","article-title":"Effect of cannabidiol on drop seizures in the Lennox\u2013Gastaut syndrome","volume":"378","author":"Devinsky","year":"2018","journal-title":"N. Engl. J. Med."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"795","DOI":"10.1007\/s40263-020-00741-5","article-title":"Critical aspects affecting cannabidiol oral bioavailability and metabolic elimination, and related clinical implications","volume":"34","author":"Perucca","year":"2020","journal-title":"CNS Drugs"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"105316","DOI":"10.1016\/j.jddst.2023.105316","article-title":"Oral delivery of cannabidiol: Revealing the formulation and absorption challenges","volume":"92","author":"Sitovs","year":"2024","journal-title":"J. Drug Deliv. Sci. Technol."},{"key":"ref_22","first-page":"81","article-title":"Cannabidiol bioavailability is nonmonotonic with a long terminal elimination half-life: A pharmacokinetic modeling-based analysis","volume":"10","author":"Kolli","year":"2025","journal-title":"Cannabis Cannabinoid Res."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"646","DOI":"10.1016\/j.jconrel.2021.08.013","article-title":"Solid self emulsifying drug delivery system: Superior mode for oral delivery of hydrophobic cargos","volume":"337","author":"Maji","year":"2021","journal-title":"J. Control. Release"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Buya, A.B., Beloqui, A., Memvanga, P.B., and Pr\u00e9at, V. (2020). Self-nano-emulsifying drug-delivery systems: From the development to the current applications and challenges in oral drug delivery. Pharmaceutics, 12.","DOI":"10.3390\/pharmaceutics12121194"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"104526","DOI":"10.1016\/j.jddst.2023.104526","article-title":"Lipid based drug delivery systems for oral, transdermal and parenteral delivery: Recent strategies for targeted delivery consistent with different clinical application","volume":"85","author":"Srivastav","year":"2023","journal-title":"J. Drug Deliv. Sci. Technol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1016\/j.apsb.2013.10.001","article-title":"Oral lipid-based drug delivery systems\u2013an overview","volume":"3","author":"Kalepu","year":"2013","journal-title":"Acta Pharm. Sin. B"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"3034","DOI":"10.5897\/AJPPX2013.0004","article-title":"Lipid-based drug delivery systems (LDDS): Recent advances and applications of lipids in drug delivery","volume":"7","author":"Chime","year":"2013","journal-title":"Afr. J. Pharm. Pharmacol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1615\/CritRevTherDrugCarrierSyst.2014008502","article-title":"Recent advances in self-emulsifying drug delivery systems (SEDDS)","volume":"31","author":"Singh","year":"2014","journal-title":"Crit. Rev.\u2122 Ther. Drug Carr. Syst."},{"key":"ref_29","first-page":"137","article-title":"A review on self emulsifying drug delivery system","volume":"2","author":"Kanjani","year":"2016","journal-title":"Asian J. Biomater. Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1811","DOI":"10.1080\/10717544.2022.2083724","article-title":"Self-emulsifying drug delivery systems: A novel approach to deliver drugs","volume":"29","author":"Salawi","year":"2022","journal-title":"Drug Deliv."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"675","DOI":"10.3109\/10717544.2014.896058","article-title":"Self-microemulsifying drug delivery system (SMEDDS)\u2013challenges and road ahead","volume":"22","author":"Dokania","year":"2015","journal-title":"Drug Deliv."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1016\/j.tifs.2021.06.046","article-title":"Self-emulsifying formulations to augment therapeutic efficacy of nutraceuticals: From concepts to clinic","volume":"115","author":"Dhritlahre","year":"2021","journal-title":"Trends Food Sci. Technol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1","DOI":"10.3109\/03639045.2012.660949","article-title":"Role of excipients in successful development of self-emulsifying\/microemulsifying drug delivery system (SEDDS\/SMEDDS)","volume":"39","author":"Rahman","year":"2013","journal-title":"Drug Dev. Ind. Pharm."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1523","DOI":"10.5740\/jaoacint.15-095","article-title":"Determination of 11 cannabinoids in biomass and extracts of different varieties of Cannabis using high-performance liquid chromatography","volume":"98","author":"Gul","year":"2015","journal-title":"J. AOAC Int."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"466","DOI":"10.1208\/s12249-015-0370-5","article-title":"Development of solid self-emulsifying formulation for improving the oral bioavailability of erlotinib","volume":"17","author":"Truong","year":"2016","journal-title":"Aaps Pharmscitech"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1208\/s12249-024-02857-z","article-title":"Formulation development and evaluation of cannabidiol hot-melt extruded solid self-emulsifying drug delivery system for oral applications","volume":"25","author":"Sanil","year":"2024","journal-title":"AAPS PharmSciTech"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"102026","DOI":"10.1016\/j.jddst.2020.102026","article-title":"Development, optimization and evaluation of losartan potassium loaded Self Emulsifying Drug Delivery System","volume":"60","author":"Kommana","year":"2020","journal-title":"J. Drug Deliv. Sci. Technol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"121159","DOI":"10.1016\/j.ijpharm.2021.121159","article-title":"Lipid-based formulations to increase cannabidiol bioavailability: In vitro digestion tests, pre-clinical assessment and clinical trial","volume":"609","author":"Vardanega","year":"2021","journal-title":"Int. J. Pharm."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"106058","DOI":"10.1016\/j.ejps.2021.106058","article-title":"Development and pharmacokinetic evaluation of a self-nanoemulsifying drug delivery system for the oral delivery of cannabidiol","volume":"168","author":"Kok","year":"2022","journal-title":"Eur. J. Pharm. Sci."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"2722","DOI":"10.1007\/s13346-024-01766-9","article-title":"Enhancement of cannabidiol oral bioavailability through the development of nanostructured lipid carriers: In vitro and in vivo evaluation studies","volume":"15","author":"Taha","year":"2025","journal-title":"Drug Deliv. Transl. Res."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1615\/CritRevTherDrugCarrierSyst.2021038490","article-title":"Recent progress in self-emulsifying drug delivery systems: A systematic patent review (2011\u2013-2020)","volume":"39","author":"Ruiz","year":"2022","journal-title":"Crit. Rev. Ther. Drug Carr. Syst."},{"key":"ref_42","unstructured":"(2025, November 18). Full Prescribing Information, Available online: https:\/\/www.accessdata.fda.gov\/drugsatfda_docs\/label\/2018\/210365lbl.pdf."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"673","DOI":"10.1016\/j.addr.2007.10.014","article-title":"Enhancing intestinal drug solubilisation using lipid-based delivery systems","volume":"60","author":"Porter","year":"2008","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"166","DOI":"10.1016\/j.ejpb.2010.12.033","article-title":"Effects of non-ionic surfactants on cytochrome P450-mediated metabolism in vitro","volume":"78","author":"Christiansen","year":"2011","journal-title":"Eur. J. Pharm. Biopharm."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1016\/j.ejps.2008.11.002","article-title":"Nonionic surfactants are strong inhibitors of cytochrome P450 3A biotransformation activity in vitro and in vivo","volume":"36","author":"Ren","year":"2009","journal-title":"Eur. J. Pharm. Sci."},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Danaei, M.R., Dehghankhold, M., Ataei, S., Hasanzadeh Davarani, F., Javanmard, R., Dokhani, A., Khorasani, S., and Mozafari, Y.M. (2018). Impact of particle size and polydispersity index on the clinical applications of lipidic nanocarrier systems. Pharmaceutics, 10.","DOI":"10.3390\/pharmaceutics10020057"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"14","DOI":"10.69857\/joapr.v13i1.704","article-title":"A paradigm shift in bioavailability enhancement using solid self emulisifying drug delivery system","volume":"13","author":"Umadevi","year":"2025","journal-title":"J. Appl. Pharm. Res."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"119379","DOI":"10.1016\/j.molliq.2022.119379","article-title":"Influence of tween nature and type on physicochemical properties and stability of spearmint essential oil (Mentha spicata L.) stabilized with basil seed mucilage nanoemulsion","volume":"359","author":"Gorjian","year":"2022","journal-title":"J. Mol. Liq."},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Alghananim, A., \u00d6zalp, Y., Mesut, B., Serakinci, N., \u00d6zsoy, Y., and G\u00fcng\u00f6r, S. (2020). A solid ultra fine self-nanoemulsifying drug delivery system (S-snedds) of deferasirox for improved solubility: Optimization, characterization, and in vitro cytotoxicity studies. Pharmaceuticals, 13.","DOI":"10.3390\/ph13080162"},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Mohite, P., Singh, S., Pawar, A., Sangale, A., and Prajapati, B.G. (2023). Lipid-based oral formulation in capsules to improve the delivery of poorly water-soluble drugs. Front. Drug Deliv., 3.","DOI":"10.3389\/fddev.2023.1232012"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1023\/B:PHAM.0000016282.77887.1f","article-title":"Drug solubilization behavior during in vitro digestion of simple triglyceride lipid solution formulations","volume":"21","author":"Kaukonen","year":"2004","journal-title":"Pharm. Res."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1016\/j.ejps.2008.09.006","article-title":"A new self-emulsifying drug delivery system (SEDDS) for poorly soluble drugs: Characterization, dissolution, in vitro digestion and incorporation into solid pellets","volume":"35","author":"Abdalla","year":"2008","journal-title":"Eur. J. Pharm. Sci."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1211\/0022357021771896","article-title":"Evaluation of the in--vitro digestion profiles of long and medium chain glycerides and the phase behaviour of their lipolytic products","volume":"54","author":"Sek","year":"2002","journal-title":"J. Pharm. Pharmacol."}],"container-title":["Biomolecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-273X\/16\/1\/21\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,23]],"date-time":"2025-12-23T11:21:31Z","timestamp":1766488891000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-273X\/16\/1\/21"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,12,23]]},"references-count":53,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,1]]}},"alternative-id":["biom16010021"],"URL":"https:\/\/doi.org\/10.3390\/biom16010021","relation":{},"ISSN":["2218-273X"],"issn-type":[{"value":"2218-273X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,12,23]]}}}